Project 2: Functional Neuroimaging of Alcoholism Vulnerability: Probing Glutamate and Reward, Using the Fyn Kinase Inhibitor Drug, Saracatinib Godfrey Pearlson, M.D. Abstract This project will test the impact of a direct manipulation of a specific, alcoholism risk-relevant mechanism involving intracellular signaling, on functional MRI-measured human reward brain circuit function. It tests the dose-related effects of the Fyn kinase (Fyn) inhibitor drug, saracatinib (AZD0530) in a placebo-controlled, double-blind, randomized, counterbalanced study design. All proposed aims for Project 2 compare family history positive for alcoholism (FHP; i.e., affected parent plus other close relatives, N=40) to matched family history negative (FHN; i.e., no affected first-degree relative, N=40) participants on four fMRI tasks, with the goal of clarifying the interplay of the neurotransmitters dopamine and glutamate via protein kinase A- related signaling pathways in reward circuit dysfunction associated with familial risk for alcoholism.